Probe for treating a tumor or the like

ABSTRACT

An article of clothing is provided for selectively destroying dividing cells in living tissue formed of dividing cells and non-dividing cells. The dividing cells contain polarizable intracellular members and during late anaphase or telophase, the dividing cells are connected to one another by a cleavage furrow. The article of clothing includes insulated electrodes to be coupled to a generator for subjecting the living tissue to electric field conditions sufficient to cause movement of the polarizable intracellular members toward the cleavage furrow in response to a non-homogeneous electric field being induced in the dividing cells. The non-homogeneous electric field produces an increased density electric field in the region of the cleavage furrow. The movement of the polarizable intracellular intracellular members towards the cleavage furrow causes the breakdown thereof which adversely impacts the multiplication of the dividing cells.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.10/285,313, filed Oct. 31, 2002, which is a continuation-in-partapplication of U.S. patent application Ser. No. 10/263,329, filed Oct.2, 2002, each of which is hereby incorporated by reference in itsentirety.

TECHNICAL FIELD

This invention concerns selective destruction of rapidly dividing cellsin a localized area, and more particularly, to an apparatus and methodfor selectively destroying dividing cells by applying an electric fieldhaving certain prescribed characteristics using an apparatus that isconfigured to be complimentary to a specific body part.

BACKGROUND

All living organisms proliferate by cell division, including cellcultures, microorganisms (such as bacteria, mycoplasma, yeast, protozoa,and other single-celled organisms), fungi, algae, plant cells, etc.Dividing cells of organisms can be destroyed, or their proliferationcontrolled, by methods that are based on the sensitivity of the dividingcells of these organisms to certain agents. For example, certainantibiotics stop the multiplication process of bacteria.

The process of eukaryotic cell division is called “mitosis”, whichinvolves nice distinct phases (see Darnell et al., Molecular CellBiology, New York: Scientific American Books, 1986, p. 149). Duringinterphase, the cell replicates chromosomal DNA, which begins condensingin early prophase. At this point, centrioles (each cell contains 2)begin moving towards opposite poles of the cell. In middle prophase,each chromosome is composed of duplicate chromatids. Microtubularspindles radiate from regions adjacent to the centrioles, which arecloser to their poles. By late prophase, the centrioles have reached thepoles, and some spindle fibers extend to the center of the cell, whileothers extend from the poles to the chromatids. The cells then move intometaphase, when the chromosomes move toward the equator of the cell andalign in the equatorial plane. Next is early anaphase, during which timedaughter chromatids separate from each other at the equator by movingalong the spindle fibers toward a centromere at opposite poles. The cellbegins to elongate along the axis of the pole; the pole-to-pole spindlesalso elongate. Late anaphase occurs when the daughter chromosomes (asthey are not called) each reach their respective opposite poles. At thispoint, cytokinesis begins as the cleavage furrow begins to form at theequator of the cell. In other words, late anaphase is the point at whichpinching the cell membrane begins. During telophase, cytokinesis isnearly complete and spindles disappear. Only a relatively narrowmembrane connection joins the two cytoplasms. Finally, the membranesseparate fully, cytokinesis is complete and the cell returns tointerphase.

In meisosis, the cell undergoes a second division, involving separationof sister chromosomes to opposite poles of the cell along spindlefibers, followed by formation of a cleavage furrow and cell division.However, this division is not preceded by chromosome replication,yielding a haploid germ cell.

Bacteria also divide by chromosome replication, followed by cellseparation. However, since the daughter chromosomes separate byattachment to membrane components; there is no visible apparatus thatcontributes to cell division as in eukaryotic cells.

It is well known that tumors, particularly malignant or canceroustumors, grow uncontrollably compared to normal tissue. Such expeditedgrowth enables tumors to occupy an ever-increasing space and to damageor destroy tissue adjacent thereto. Furthermore, certain cancers arecharacterized by an ability to transmit cancerous “seeds”, includingsingle cells or small cell clusters (metastases), to new locations wherethe metastatic cancer cells grow into additional tumors.

The rapid growth of tumors, in general, and malignant tumors inparticular, as described above, is the result of relatively frequentcell division or multiplication of these cells compared to normal tissuecells. The distinguishably frequent cell division of cancer cells is thebasis for the effectiveness of existing cancer treatments, e.g.,irradiation therapy and the use of various chemotherapeutic agents. Suchtreatments are based on the fact that cells undergoing division are moresensitive to radiation and chemotherapeutic agents than non-dividingcells. Because tumors cells divide much more frequently than normalcells, it is possible, to a certain extent, to selectively damage ordestroy tumor cells by radiation therapy and/or chemotherapy. The actualsensitivity of cells to radiation, therapeutic agents, etc., is alsodependent on specific characteristics of different types of normal ormalignant cell types. Thus, unfortunately, the sensitivity of tumorcells is not sufficiently higher than that many types of normal tissues.This diminishes the ability to distinguish between tumor cells andnormal cells, and therefore, existing cancer treatments typically causesignificant damage to normal tissues, thus limiting the therapeuticeffectiveness of such treatments. Furthermore, the inevitable damage toother tissue renders treatments very traumatic to the patients and,often, patients are unable to recover from a seemingly successfultreatment. Also, certain types of tumors are not sensitive at all toexisting methods of treatment.

There are also other methods for destroying cells that do not rely onradiation therapy or chemotherapy alone. For example, ultrasonic andelectrical methods for destroying tumor cells can be used in addition toor instead of conventional treatments. Electric fields and currents havebeen used for medical purposes for many years. The most common is thegeneration of electric currents in a human or animal body by applicationof an electric field by means of a pair of conductive electrodes betweenwhich a potential difference is maintained. These electric currents areused either to exert their specific effects, i.e., to stimulateexcitable tissue, or to generate heat by flowing in the body since itacts as a resistor. Examples of the first type of application includethe following: cardiac defibrillators, peripheral nerve and musclestimulators, brain stimulators, etc. Currents are used for heating, forexample, in devices for tumor ablation, ablation of malfunctioningcardiac or brain tissue, cauterization, relaxation of muscle rheumaticpain and other pain, etc.

Another use of electric fields for medical purposes involves theutilization of high frequency oscillating fields transmitted from asource that emits an electric wave, such as an RF wave or a microwavesource that is directed at the part of the body that is of interest(i.e., target). In these instances, there is no electric energyconduction between the source and the body; but rather, the energy istransmitted to the body by radiation or induction. More specifically,the electric energy generated by the source reaches the vicinity of thebody via a conductor and is transmitted from it through air or someother electric insulating material to the human body.

In a conventional electrical method, electrical current is delivered toa region of the target tissue using electrodes that are placed incontact with the body of the patient. The applied electrical currentdestroys substantially all cells in the vicinity of the target tissue.Thus, this type of electrical method does not discriminate betweendifferent types of cells within the target tissue and results in thedestruction of both tumor cells and normal cells.

Electric fields that can be used in medical applications can thus beseparated generally into two different modes. In the first mode, theelectric fields are applied to the body or tissues by means ofconducting electrodes. These electric fields can be separated into twotypes, namely (1) steady fields or fields that change at relatively slowrates, and alternating fields of low frequencies that inducecorresponding electric currents in the body or tissues, and (2) highfrequency alternating fields (above 1 MHz) applied to the body by meansof the conducting electrodes. In the second mode, the electric fieldsare high frequency alternating fields applied to the body by means ofinsulated electrodes.

The first type of electric field is used, for example, to stimulatenerves and muscles, pace the heart, etc. In fact, such fields are usedin nature to propagate signals in nerve and muscle fibers, centralnervous system (CNS), heart, etc. The recording of such natural fieldsis the basis for the ECG, EEG, EMG, ERG, etc. The field strength inthese applications, assuming a medium of homogenous electric properties,is simply the voltage applied to the stimulating/recording electrodesdivided by the distance between them. These currents can be calculatedby Ohm's law and can have dangerous stimulatory effects on the heart andCNS and can result in potentially harmful ion concentration changes.Also, if the currents are strong enough, they can cause excessiveheating in the tissues. This heating can be calculated by the powerdissipated in the tissue (the product of the voltage and the current).

When such electric fields and currents are alternating, theirstimulatory power, on nerve, muscle, etc., is an inverse function of thefrequency. At frequencies above 1-10 KHz, the stimulation power of thefields approaches zero. This limitation is due to the fact thatexcitation induced by electric stimulation is normally mediated bymembrane potential changes, the rate of which is limited by the RCproperties (time constants on the order of 1 ms) of the membrane.

Regardless of the frequency, when such current inducing fields areapplied, they are associated with harmful side effects caused bycurrents. For example, one negative effect is the changes in ionicconcentration in the various “compartments” within the system, and theharmful products of the electrolysis taking place at the electrodes, orthe medium in which the tissues are imbedded. The changes in ionconcentrations occur whenever the system includes two or morecompartments between which the organism maintains ion concentrationdifferences. For example, for most tissues, [Ca⁺⁺] in the extracellularfluid is about 2×10⁻³ M, while in the cytoplasm of typical cells itsconcentration can be as low as 10⁻⁷ M. A current induced in such asystem by a pair of electrodes, flows in part from the extracellularfluid into the cells and out again into the extracellular medium. About2% of the current flowing into the cells is carried by the Ca.⁺⁺ ions.In contrast, because the concentration of intracellular Ca⁺⁺ is muchsmaller, only a negligible fraction of the currents that exits the cellsis carried by these ions. Thus, Ca⁺⁺ ions accumulate in the cells suchthat their concentrations in the cells increases, while theconcentration in the extracellular compartment may decrease. Theseeffects are observed for both DC and alternating currents (AC). The rateof accumulation of the ions depends on the current intensity ionmobilities, membrane ion conductance, etc. An increase in [Ca⁺⁺] isharmful to most cells and if sufficiently high will lead to thedestruction of the cells. Similar considerations apply to other ions. Inview of the above observations, long term current application to livingorganisms or tissues can result in significant damage. Another majorproblem that is associated with such electric fields, is due to theelectrolysis process that takes place at the electrode surfaces. Herecharges are transferred between the metal (electrons) and theelectrolytic solution (ions) such that charged active radicals areformed. These can cause significant damage to organic molecules,especially macromolecules and thus damage the living cells and tissues.

In contrast, when high frequency electric fields, above 1 MHz andusually in practice in the range of GHz, are induced in tissues by meansof insulated electrodes, the situation is quite different. These type offields generate only capacitive or displacement currents, rather thanthe conventional charge conducting currents. Under the effect of thistype of field, living tissues behave mostly according to theirdielectric properties rather than their electric conductive properties.Therefore, the dominant field effect is that due to dielectric lossesand heating. Thus, it is widely accepted that in practice, themeaningful effects of such fields on living organisms, are only thosedue to their heating effects, i.e., due to dielectric losses.

In U.S. Pat. No. 6,043,066 ('066) to Mangano, a method and device arepresented which enable discrete objects having a conducting inner core,surrounded by a dielectric membrane to be selectively inactivated byelectric fields via irreversible breakdown of their dielectric membrane.One potential application for this is in the selection and purging ofcertain biological cells in a suspension. According to the '066 patent,an electric field is applied for targeting selected cells to causebreakdown of the dielectric membranes of these tumor cells, whilepurportedly not adversely affecting other desired subpopulations ofcells. The cells are selected on the basis of intrinsic or induceddifferences in a characteristic electroporation threshold. Thedifferences in this threshold can depend upon a number of parameters,including the difference in cell size.

The method of the '066 patent is therefore based on the assumption thatthe electroporation threshold of tumor cells is sufficientlydistinguishable from that of normal cells because of differences in cellsize and differences in the dielectric properties of the cell membranes.Based upon this assumption, the larger size of many types of tumor cellsmakes these cells more susceptible to electroporation and thus, it maybe possible to selectively damage only the larger tumor cell membranesby applying an appropriate electric field. One disadvantage of thismethod is that the ability to discriminate is highly dependent upon celltype, for example, the size difference between normal cells and tumorcells is significant only in certain types of cells. Another drawback ofthis method is that the voltages which are applied can damage some ofthe normal cells and may not damage all of the tumor cells because thedifferences in size and membrane dielectric properties are largelystatistical and the actual cell geometries and dielectric properties canvary significantly.

What is needed in the art and has heretofore not been available is anapparatus for destroying dividing cells, wherein the apparatus betterdiscriminates between dividing cells, including single-celled organisms,and non-dividing cells and is capable of selectively destroying thedividing cells or organisms with substantially no affect on thenon-dividing cells or organisms and which can be configured to appliedto a specific body part, such as an extremity and thus lends itself tobeing incorporated into an article of clothing.

SUMMARY

An apparatus for use in a number of different applications forselectively destroying cells undergoing growth and division is provided.This includes, cell, particularly tumor cells, in living tissue andsingle-celled organisms. The apparatus can be incorporated into a numberof different configurations that are specifically designed to beeffective for specific body parts so that the apparatus distinctlytargets a localized area to eliminate or control the growth of suchliving tissue or organisms. For example and as will be described ingreater detail hereinafter, the apparatus is particularly capable ofbeing incorporated into a piece of clothing that is worn over the tumorarea. One of the configurations of the apparatus is in the form of ahat, cap or other type of structure to be fitted over a person's headfor treating intra-cranial tumors, external scalp lesions or otherlesions. In another configuration, the apparatus is in the form of amodified bra or the like to be fitted over breasts for treating breastcancer or other type of tumor condition. In addition, the apparatus canbe incorporated into clothing that is to be worn over other body parts,such as testicles, a hand, leg, arm, neck, etc., for treating alocalized tumor in one of these locations (body parts). For example, ahigh standing collar member or necklace type structure can be used totreat thyroid, parathyroid, laryngeal lesions, etc. In this embodiment,the apparatus (either completely or partially) is disposed withinclothing that is fit around the neck for treating these conditions. Inanother aspect, localized treatment is provided by the apparatus when itis in the form of an internal member (e.g., a probe or catheter) that isinserted into the body through a natural pathway, such as the urethra,vagina, etc., or the member can penetrate the skin to and other tissuesto reach an internal target.

A major use of the present apparatus is in the treatment of tumors byselective destruction of tumor cells with substantially no affect onnormal tissue cells, and thus, the exemplary apparatus is describedbelow in the context of selective destruction of tumor cells. It shouldbe appreciated however, that for purpose of the following description,the term “cell” may also refer to a single-celled organism (eubacteria,bacteria, yeast, protozoa), multi-celled organisms (fungi, algae, mold),and plants as or parts thereof that are not normally classified as“cells”. The exemplary apparatus enables selective destruction of cellsundergoing division in a way that is more effective and more accurate(e.g., more adaptable to be aimed at specific targets) than existingmethods. Further, the present apparatus causes minimal damage, if any,to normal tissue and, thus, reduces or eliminates many side-effectsassociated with existing selective destruction methods, such asradiation therapy and chemotherapy. The selective destruction ofdividing cells using the present apparatus does not depend on thesensitivity of the cells to chemical agents or radiation. Instead, theselective destruction of dividing cells is based on distinguishablegeometrical characteristics of cells undergoing division, in comparisonto non-dividing cells, regardless of the cell geometry of the type ofcells being treated.

According to one exemplary embodiment, cell geometry-dependent selectivedestruction of living tissue is performed by inducing a non-homogenouselectric field in the cells using an electronic apparatus.

It has been observed by the present inventor that, while different cellsin their non-dividing state may have different shapes, e.g., spherical,ellipsoidal, cylindrical, “pancake-like”, etc., the division process ofpractically all cells is characterized by development of a “cleavagefurrow” in late anaphase and telophase. This cleavage furrow is a slowconstriction of the cell membrane (between the two sets of daughterchromosomes) which appears microscopically as a growing cleft (e.g., agroove or notch) that gradually separates the cell into two new cells.During the division process, there is a transient period (telophase)during which the cell structure is basically that of two sub-cellsinterconnected by a narrow “bridge” formed of the cell material. Thedivision process is completed when the “bridge” between the twosub-cells is broken. The selective destruction of tumor cells using thepresent electronic apparatus utilizes this unique geometrical feature ofdividing cells.

When a cell or a group of cells are under natural conditions orenvironment, i.e., part of a living tissue, they are disposed surroundedby a conductive environment consisting mostly of an electrolyticinter-cellular fluid and other cells that are composed mostly of anelectrolytic intra-cellular liquid. When an electric field is induced inthe living tissue, by applying an electric potential across the tissue;an electric field is formed in the tissue and the specific distributionand configuration of the electric field lines defines the direction ofcharge displacement, or paths of electric currents in the tissue, ifcurrents are in fact induced in the tissue. The distribution andconfiguration of the electric field is dependent on various parametersof the tissue, including the geometry and the electric properties of thedifferent tissue components, and the relative conductivities, capacitiesand dielectric constants (that may be frequency dependent) of the tissuecomponents.

The electric current flow pattern for cells undergoing division is verydifferent and unique as compared to non-dividing cells. Such cellsincluding first and second sub-cells, namely an “original” cell and anewly formed cell, that are connected by a cytoplasm “bridge” or “neck”.The currents penetrate the first sub-cell through part of the membrane(“the current source pole”); however, they do not exit the firstsub-cell through a portion of its membrane closer to the opposite pole(“the current sink pole”). Instead, the lines of current flow convergeat the neck or cytoplasm bridge, whereby the density of the current flowlines is greatly increased. A corresponding, “mirror image”, processthat takes place in the second sub-cell, whereby the current flow linesdiverge to a lower density configuration as they depart from the bridge,and finally exit the second sub-cell from a part of its membrane closesto the current sink.

When a polarizable object is placed in a non-uniform converging ordiverging field, electric forces act on it and pull it towards thehigher density electric field lines. In the case of dividing cell,electric forces are exerted in the direction of the cytoplasm bridgebetween the two cells. Since all intercellular organelles andmacromolecules are polarizable, they are all force towards the bridgebetween the two cells. The field polarity is irrelevant to the directionof the force and, therefore, an alternating electric having specificproperties can be used to produce substantially the same effect. It willalso be appreciated that the concentrated and inhomogeneous electricfield present in or near the bridge or neck portion in itself exertsstrong forces on charges and natural dipoles and can lead to thedisruption of structures associated with these members.

The movement of the cellular organelles towards the bridge disrupts thecell structure and results in increased pressure in the vicinity of theconnecting bridge membrane. This pressure of the organelles on thebridge membrane is expected to break the bridge membrane and, thus, itis expected that the dividing cell will “explode” in response to thispressure. The ability to break the membrane and disrupt other cellstructures can be enhanced by applying a pulsating alternating electricfield that has a frequency from about 50 KHz to about 500 KHz. When thistype of electric field is applied to the tissue, the forces exerted onthe intercellular organelles have a “hammering” effect, whereby forcepulses (or beats) are applied to the organelles numerous times persecond, enhancing the movement of organelles of different sizes andmasses towards the bridge (or neck) portion from both of the sub-cells,thereby increasing the probability of breaking the cell membrane at thebridge portion. The forces exerted on the intracellular organelles alsoaffect the organelles themselves and may collapse or break theorganelles.

According to one exemplary embodiment, the apparatus for applying theelectric field is an electronic apparatus that generates the desiredelectric signals in the shape of waveforms or trains of pulses. Theelectronic apparatus includes a generator that generates an alternatingvoltage waveform at frequencies in the range from about 50 KHz to about500 KHz. The generator is operatively connected to conductive leadswhich are connected at their other ends to insulatedconductors/electrodes (also referred to as isolects) that are activatedby the generated waveforms. The insulated electrodes consist of aconductor in contact with a dielectric (insulating layer) that is incontact with the conductive tissue, thus forming a capacitor. Theelectric fields that are generated by the present apparatus can beapplied in several different modes depending upon the precise treatmentapplication.

In one exemplary embodiment, the electric fields are applied by externalinsulated electrodes which are incorporated into an article of clothingand which are constructed so that the applied electric fields are of alocal type that target a specific, localized area of tissue (e.g., atumor). This embodiment is designed to treat tumors and lesions that areat or below the skin surface by wearing the article of clothing over thetarget tissue so that the electric fields generated by the insulatedelectrodes are directed at the tumors (lesions, etc.).

According to another embodiment, the apparatus is used in an internaltype application in that the insulated electrodes are in the form of aprobe or catheter etc., that enter the body through natural pathways,such as the urethra or vagina, or are configured to penetrate livingtissue, until the insulated electrodes are positioned near the internaltarget area (e.g., an internal tumor).

Thus, the present apparatus utilizes electric fields that fall into aspecial intermediate category relative to previous high and lowfrequency applications in that the present electric fields arebio-effective fields that have no meaningful stimulatory effects and nothermal effects. Advantageously, when non-dividing cells are subjectedto these electric fields, there is no effect on the cells; however, thesituation is much different when dividing cells are subjected to thepresent electric fields. Thus, the present electronic apparatus and thegenerated electric fields target dividing cells, such as tumors or thelike, and do not target non-dividing cells that is found around inhealthy tissue surrounding the target area. Furthermore, since thepresent apparatus utilizes insulated electrodes, the above mentionednegative effects, obtained when conductive electrodes are used, i.e.,ion concentration changes in the cells and the formation of harmfulagents by electrolysis, do not occur with the present apparatus. This isbecause, in general, no actual transfer of charges takes place betweenthe electrodes and the medium, and there is no charge flow in the mediumwhere the currents are capacitive.

It should be appreciated that the present electronic apparatus can alsobe used in applications other than treatment of tumors in the livingbody. In fact, the selective destruction utilizing the present apparatuscan be used in conjunction with any organism that proliferates divisionand multiplication, for example, tissue cultures, microorganisms, suchas bacteria, mycoplasma, protozoa, fungi, algae, plant cells, etc. Suchorganisms divide by the formation of a groove or cleft as describedabove. As the groove or cleft deepens, a narrow bridge is formed betweenthe two parts of the organism, similar to the bridge formed between thesub-cells of dividing animal cells. Since such organisms are covered bya membrane having a relatively low electric conductivity, similar to ananimal cell membrane described above, the electric field lines in adividing organism converge at the bridge connecting the two parts of thedividing organism. The converging field lines result in electric forcesthat displace polarizable elements and charges within the dividingorganism.

The above, and other objects, features and advantages of the presentapparatus will become apparent from the following description read inconjunction with the accompanying drawings, in which like referencenumerals designate the same elements.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIGS. 1A-1E are simplified, schematic, cross-sectional, illustrations ofvarious stages of a cell division process;

FIGS. 2A and 2B are schematic illustrations of a non-dividing cell beingsubjected to an electric field;

FIGS. 3A, 3B and 3C are schematic illustrations of a dividing cell beingsubjected to an electric field according to one exemplary embodiment,resulting in destruction of the cell (FIG. 3C) in accordance with oneexemplary embodiment;

FIG. 4 is a schematic illustration of a dividing cell at one stage beingsubject to an electric field;

FIG. 5 is a schematic block diagram of an apparatus for applying anelectric according to one exemplary embodiment for selectivelydestroying cells;

FIG. 6 is a simplified schematic diagram of an equivalent electriccircuit of insulated electrodes of the apparatus of FIG. 5;

FIG. 7 is a cross-sectional illustration of a skin patch incorporatingthe apparatus of FIG. 5 and for placement on a skin surface for treatinga tumor or the like;

FIG. 8 is a cross-sectional illustration of the insulated electrodesimplanted within the body for treating a tumor or the like;

FIG. 9 is a cross-sectional illustration of the insulated electrodesimplanted within the body for treating a tumor or the like;

FIGS. 10A-10D are cross-sectional illustrations of various constructionsof the insulated electrodes of the apparatus of FIG. 5;

FIG. 11 is a front elevational view in partial cross-section of twoinsulated electrodes being arranged about a human torso for treatment ofa tumor container within the body, e.g., a tumor associated with lungcancer;

FIGS. 12A-12C are cross-sectional illustrations of various insulatedelectrodes with and without protective members formed as a part of theconstruction thereof;

FIG. 13 is a schematic diagram of insulated electrodes that are arrangedfor focusing the electric field at a desired target while leaving otherareas in low field density (i.e., protected areas);

FIG. 14 is a cross-sectional view of insulated electrodes incorporatedinto a hat according to a first embodiment for placement on a head fortreating an intra-cranial tumor or the like;

FIG. 15 is a partial section of a hat according to an exemplaryembodiment having a recessed section for receiving one or more insulatedelectrodes;

FIG. 16 is a cross-sectional view of the hat of FIG. 15 placed on a headand illustrating a biasing mechanism for applying a force to theinsulated electrode to ensure the insulated electrode remains in contactagainst the head;

FIG. 17 is a cross-sectional top view of an article of clothing havingthe insulated electrodes incorporated therein for treating a tumor orthe like;

FIG. 18 is a cross-sectional view of a section of the article ofclothing of FIG. 17 illustrating a biasing mechanism for biasing theinsulated electrode in direction to ensure the insulated electrode isplaced proximate to a skin surface where treatment is desired;

FIG. 19 is a cross-sectional view of a probe according to one embodimentfor being disposed internally within the body for treating a tumor orthe like; and

FIG. 20 is an elevational view of an unwrapped collar according to oneexemplary embodiment for placement around a neck for treating a tumor orthe like in this area when the collar is wrapped around the neck.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Reference is made to FIGS. 1A-1E which schematically illustrate variousstages of a cell division process. FIG. 1A illustrates a cell 10 at itsnormal geometry, which can be generally spherical (as illustrated in thedrawings), ellipsoidal, cylindrical, “pancake-like” or any other cellgeometry, as is known in the art. FIGS. 1B-1D illustrate cell 10 duringdifferent stages of its division process, which results in the formationof two new cells 18 and 20, shown in FIG. 1E.

As shown in FIGS. 1B-1D, the division process of cell 10 ischaracterized by a slowly growing cleft 12 which gradually separatescell 10 into two units, namely sub-cells 14 and 16, which eventuallyevolve into new cells 18 and 20 (FIG. 1E). A shown specifically in FIG.1D, the division process is characterized by a transient period duringwhich the structure of cell 10 is basically that of the two sub-cells 14and 16 interconnected by a narrow “bridge” 22 containing cell material(cytoplasm surrounded by cell membrane).

Reference is now made to FIGS. 2A and 2B, which schematically illustratenon-dividing cell 10 being subjected to an electric field produced byapplying an alternating electric potential, at a relatively lowfrequency and at a relatively high frequency, respectively. Cell 10includes intracellular organelles, e.g., a nucleus 30. Alternatingelectric potential is applied across electrodes 28 and 32 that can beattached externally to a patient at a predetermined region, e.g., in thevicinity of the tumor being treated. When cell 10 is under naturalconditions, i.e., part of a living tissue, it is disposed in aconductive environment (hereinafter referred to as a “volume conductor”)consisting mostly of electrolytic inter-cellular liquid. When anelectric potential is applied across electrodes 28 and 32, some of thefield lines of the resultant electric field (or the current induced inthe tissue in response to the electric field) penetrate the cell 10,while the rest of the field lines (or induced current) flow in thesurrounding medium. The specific distribution of the electric fieldlines, which is substantially consistent with the direction of currentflow in this instance, depends on the geometry and the electricproperties of the system components, e.g., the relative conductivitiesand dielectric constants of the system components, that can be frequencydependent. For low frequencies, e.g., frequencies lower than 10 KHz, theconductance properties of the components completely dominate the currentflow and the field distribution, and the field distribution is generallyas depicted in FIG. 2A. At higher frequencies, e.g., at frequencies ofbetween 10 KHz and 1 MHz, the dielectric properties of the componentsbecomes more significant and eventually dominate the field distribution,resulting in field distribution lines as depicted generally in FIG. 2B.

For constant (i.e., DC) electric fields or relatively low frequencyalternating electric fields, for example, frequencies under 10 KHz, thedielectric properties of the various components are not significant indetermining and computing the field distribution. Therefore, as a firstapproximation, with regard to the electric field distribution, thesystem can be reasonably represented by the relative impedances of itsvarious components. Using this approximation, the intercellular (i.e.,extracellular) fluid and the intracellular fluid each has a relativelylow impedance, while the cell membrane 11 has a relatively highimpedance. Thus, under low frequency conditions, only a fraction of theelectric field lines (or currents induced by the electric field)penetrate membrane 11 of the cell 10. At relatively high frequencies(e.g., 10 KHz-1 MHz), in contrast, the impedance of membrane 11 relativeto the intercellular and intracellular fluids decreases, and thus, thefraction of currents penetrating the cells increases significantly. Itshould be noted that at very high frequencies, i.e., above 1 MHz, themembrane capacitance can short the membrane resistance and, therefore,the total membrane resistance can become negligible.

In any of the embodiments described above, the electric field lines (orinduced currents) penetrate cell 10 from a portion of the membrane 11closest to one of the electrodes generating the current, e.g., closestto positive electrode 28 (also referred to herein as “source”). Thecurrent flow pattern across cell 10 is generally uniform because, underthe above approximation, the field induced inside the cell issubstantially homogeneous. The currents exit cell 10 through a portionof membrane 11 closest to the opposite electrode, e.g., negativeelectrode 32 (also referred to herein as “sink”).

The distinction between field lines and current flow can depend on anumber of factors, for example, on the frequency of the applied electricpotential and on whether electrodes 28 and 32 are electricallyinsulated. For insulated electrodes applying a DC or low frequencyalternating voltage, there is practically no current flow along thelines of the electric field. At higher frequencies, the displacementcurrents are induced in the tissue due to charging and discharging ofthe electrode insulation and the cell membranes (which act as capacitorsto a certain extent), and such currents follow the lines of the electricfield. Fields generated by non-insulated electrodes, in contrast, alwaysgenerate some form of current flow, specifically, DC or low frequencyalternating fields generate conductive current flow along the fieldlines, and high frequency alternating fields generate both conductionand displacement currents along the field lines. It should beappreciated, however, that movement of polarizable intracellularorganelles according to the present invention (as described below) isnot dependent on actual flow of current and, therefore, both insulatedand non-insulated electrodes can be used efficiently. Several advantagesof insulated electrodes are that they have lower power consumption andcause less heating of the treated regions.

According to one exemplary embodiment of the present invention, theelectric fields that are used are alternating fields having frequenciesthat are in the range from about 50 KHz to about 500 KHz, and preferablyfrom about 100 KHz to about 300 KHz. For ease of discussion, these typeof electric fields are also referred to below as “TC fields”, which isan abbreviation of “Tumor Curing electric fields”, since these electricfields fall into an intermediate category (between high and lowfrequency ranges) that have bio-effective field properties while havingno meaningful stimulatory and thermal effects. These frequencies aresufficiently low so that the system behavior is determined by thesystem's Ohmic (conductive) properties but sufficiently high enough notto have any stimulation effect on excitable tissues. Such a systemconsists of two types of elements, namely, the intercellular, orextracellular fluid, or medium and the individual cells. Theintercellular fluid is mostly an electrolyte with a specific resistanceof about 40-100 Ohm*cm. As mentioned above, the cells are characterizedby three elements, namely (1) a thin, highly electric resistive membranethat coats the cell; (2) internal cytoplasm that is mostly anelectrolyte that contains numerous macromolecules and micro-organelles,including the nucleus; and (3) membranes, similar in their electricproperties to the cell membrane, cover the micro-organelles.

When this type of system is subjected to the present TC fields (e.g.,alternating electric fields in the frequency range of 100 KHz-300 KHz)most of the lines of the electric field and currents tend away from thecells because of the high resistive cell membrane and therefore thelines remain in the extracellular conductive medium. In the aboverecited frequency range, the actual fraction of electric field orcurrents that penetrates the cells is a strong function of thefrequency.

FIG. 2 schematically depicts the resulting field distribution in thesystem. As illustrated, the lines of force, which also depict the linesof potential current flow across the cell volume mostly in parallel withthe undistorted lines of force (the main direction of the electricfield). In other words, the field inside the cells is mostlyhomogeneous. In practice, the fraction of the field or current thatpenetrates the cells is determined by the cell membrane impedance valuerelative to that of the extracellular fluid. Since the equivalentelectric circuit of the cell membrane is that of a resistor andcapacitor in parallel, the impedance is a function of the frequency. Thehigher the frequency, the lower the impedance, the larger the fractionof penetrating current and the smaller the field distortion.

As previously mentioned, when cells are subjected to relatively weakelectric fields and currents that alternate at high frequencies, such asthe present TC fields having a frequency in the range of 50 KHz-500 KHz,they have no effect on the non-dividing cells. While the present TCfields have no detectable effect on such systems, the situation becomesdifferent in the presence of dividing cells.

Reference is now made to FIGS. 3A-3C which schematically illustrate theelectric current flow pattern in cell 10 during its division process,under the influence of alternating fields (TC fields) in the frequencyrange from about 100 KHz to about 300 KHz in accordance with oneexemplary embodiment. The field lines or induced currents penetrate cell10 through a part of the membrane of sub-cell 16 closer to electrode 28.However, they do not exit through the cytoplasm bridge 22 that connectssub-cell 16 with the newly formed yet still attached sub-cell 14, orthrough a part of the membrane in the vicinity of the bridge 22.Instead, the electric field or current flow lines—that are relativelywidely separated in sub-cell 16—converge as they approach bridge 22(also referred to as “neck” 22) and, thus, the current/field linedensity within neck 22 is increased dramatically. A “mirror image”process takes place in sub-cell 14, whereby the converging field linesin bridge 22 diverge as they approach the exit region of sub-cell 14.

It should be appreciated by persons skilled in the art that homogeneouselectric fields do not exert a force on electrically neutral objects,i.e., objects having substantially zero net charge, although suchobjects can become polarized. However, under a non-uniform, convergingelectric field, as shown in FIGS. 3A-3C, electric forces are exerted onpolarized objects, moving them in the direction of the higher densityelectric field lines. It will be appreciated that the concentratedelectric field that is present in the neck or bridge area in itselfexerts strong forces on charges and natural dipoles and can disruptstructures that are associated therewith. One will understand thatsimilar net forces act on charges in an alternating field, again in thedirection of the field of higher intensity.

In the configuration of FIGS. 3A and 3B, the direction of movement ofpolarized and charged objects is towards the higher density electricfield lines, i.e., towards the cytoplasm bridge 22 between sub-cells 14and 16. It is known in the art that all intracellular organelles, forexample, nuclei 24 and 26 of sub-cells 14 and 16, respectively, arepolarizable and, thus, such intracellular organelles are electricallyforced in the direction of the bridge 22. Since the movement is alwaysfrom lower density currents to the higher density currents, regardlessof the field polarity, the forces applied by the alternating electricfield to organelles, such as nuclei 24 and 26, are always in thedirection of bridge 22. A comprehensive description of such forces andthe resulting movement of macromolecules of intracellular organelles, aphenomenon referred to as “dielectrophoresis” is described extensivelyin literature, e.g., in C. L. Asbury & G. van den Engh, Biophys. J. 74,1024-1030, 1998, the disclosure of which is hereby incorporated byreference in its entirety.

The movement of the organelles 24 and 26 towards the bridge 22 disruptsthe structure of the dividing cell, change the concentration of thevarious cell constituents and, eventually, the pressure of theconverging organelles on bridge membrane 22 results in the breakage ofcell membrane 11 at the vicinity of the bridge 22, as shownschematically in FIG. 3C. The ability to break membrane 11 at bridge 22and to otherwise disrupt the cell structure and organization can beenhanced by applying a pulsating AC electric field, rather than a steadyAC field. When a pulsating field is applied, the forces acting onorganelles 24 and 26 have a “hammering” effect, whereby pulsed forcesbeat on the intracellular organelles towards the neck 22 from bothsub-cells 14 and 16, thereby increasing the probability of breaking cellmembrane 11 in the vicinity of neck 22.

A very important element, which is very susceptible to the specialfields that develop within the dividing cells is the microtubule spindlethat plays a major role in the division process. In FIG. 4, a dividingcell 10 is illustrated, at an earlier stage as compared to FIGS. 3A and3B, under the influence of external TC fields (e.g., alternating fieldsin the frequency range of about 100 KHz to about 300 KHz), generallyindicated as lines 100, with a corresponding spindle mechanism generallyindicated at 120. The lines 120 are microtubules that are known to havea very strong dipole moment. This strong polarization makes the tubulessusceptible to electric fields. Their positive charges are located atthe two centrioles while two sets of negative poles are at the center ofthe dividing cell and the other pair is at the points of attachment ofthe microtubules to the cell membrane, generally indicated at 130. Thisstructure forms sets of double dipoles and therefore they aresusceptible to fields of different directions. It will be understoodthat the effect of the TC fields on the dipoles does not depend on theformation of the bridge (neck) and thus, the dipoles are influenced bythe TC fields prior to the formation of the bridge (neck).

Since the present apparatus (as will be described in greater detailbelow) utilizes insulated electrodes, the above-mentioned negativeeffects obtained when conductive electrodes are used, i.e., ionconcentration changes in the cells and the formation of harmful agentsby electrolysis, do not occur when the present apparatus is used. Thisis because, in general, no actual transfer of charges takes placebetween the electrodes and the medium and there is no charge flow in themedium where the currents are capacitive, i.e., are expressed only asrotation of charges, etc.

Turning now to FIG. 5, the TC fields described above that have beenfound to advantageously destroy tumor cells are generated by anelectronic apparatus 200. FIG. 5 is a simple schematic diagram of theelectronic apparatus 200 illustrating the major components thereof. Theelectronic apparatus 200 generates the desired electric signals (TCsignals) in the shape of waveforms or trains of pulses. The apparatus200 includes a generator 210 and a pair of conductive leads 220 that areattached at one end thereof to the generator 210. The opposite ends ofthe leads 220 are connected to insulated conductors 230 that areactivated by the electric signals (e.g., waveforms). The insulatedconductors 230 are also referred to hereinafter as isolects 230.Optionally and according to another exemplary embodiment, the apparatus200 includes a temperature sensor 240 and a control box 250 which areboth added to control the amplitude of the electric field generated soas not to generate excessive heating in the area that is treated.

The generator 210 generates an alternating voltage waveform atfrequencies in the range from about 50 KHz to about 500 KHz (preferablyfrom about 100 KHz to about 300 KHz) (i.e., the TC fields). The requiredvoltages are such that the electric field intensity in the tissue to betreated is in the range of about 0.1 V/cm to about 10 V/cm. To achievethis field, the actual potential difference between the two conductorsin the isolects 230 is determined by the relative impedances of thesystem components, as described below.

When the control box 250 is included, it controls the output of thegenerator 210 so that it will remain constant at the value preset by theuser or the control box 250 sets the output at the maximal value thatdoes not cause excessive heating, or the control box 250 issues awarning or the like when the temperature (sensed by temperature sensor240) exceeds a preset limit.

The leads 220 are standard isolated conductors with a flexible metalshield, preferably grounded so that it prevents the spread of theelectric field generated by the leads 220. The isolects 230 havespecific shapes and positioning so as to generate an electric field ofthe desired configuration, direction and intensity at the target volumeand only there so as to focus the treatment.

The specifications of the apparatus 200 as a whole and its individualcomponents are largely influenced by the fact that at the frequency ofthe present TC fields (50 KHz-500 KHz), living systems behave accordingto their “Ohmic”, rather than their dielectric properties. The onlyelements in the apparatus 200 that behave differently are the insulatorsof the isolects 230 (see FIGS. 7-9). The isolects 200 consist of aconductor in contact with a dielectric that is in contact with theconductive tissue thus forming a capacitor.

The details of the construction of the isolects 230 is based on theirelectric behavior that can be understood from their simplified electriccircuit when in contact with tissue as generally illustrated in FIG. 6.In the illustrated arrangement, the potential drop or the electric fielddistribution between the different components is determined by theirrelative electric impedance, i.e., the fraction of the field on eachcomponent is given by the value of its impedance divided by the totalcircuit impedance. For example, the potential drop on element ?V_(A)=A/(A+B+C+D+E). Thus, for DC or low frequency AC, practically allthe potential drop is on the capacitor (that acts as an insulator). Forrelatively very high frequencies, the capacitor practically is a shortand therefore, practically all the field is distributed in the tissues.At the frequencies of the present TC fields (e.g., 50 KHz to 500 KHz),which are intermediate frequencies, the impedance of the capacitance ofthe capacitors is dominant and determines the field distribution.Therefore, in order to increase the effective voltage drop across thetissues (field intensity), the impedance of the capacitors is to bedecreased (i.e., increase their capacitance). This can be achieved byincreasing the effective area of the “plates” of the capacitor, decreasethe thickness of the dielectric or use a dielectric with high dielectricconstant.

In order to optimize the field distribution, the isolects 230 areconfigured differently depending upon the application in which theisolects 230 are to be used. There are two principle modes for applyingthe present electric fields (TC fields). First, the TC fields can beapplied by external isolects and second, the TC fields can be applied byinternal isolects.

Electric fields (TC fields) that are applied by external isolects can beof a local type or widely distributed type. The first type includes, forexample, the treatment of skin tumors and treatment of lesions close tothe skin surface. FIG. 7 illustrates an exemplary embodiment where theisolects 230 are incorporated in a skin patch 300. The skin patch 300can be a self-adhesive flexible patch with one or more pairs of isolects230. The patch 300 includes internal insulation 310 (formed of adielectric material) and the external insulation 260 and is applied toskin surface 301 that contains a tumor 303 either on the skin surface301 or slightly below the skin surface 301. Tissue is generallyindicated at 305. To prevent the potential drop across the internalinsulation 310 to dominate the system, the internal insulation 310 musthave a relatively high capacity. This can be achieved by a large surfacearea; however, this may not be desired as it will result in the spreadof the field over a large area (e.g., an area larger than required totreat the tumor). Alternatively, the internal insulation 310 can be madevery thin and/or the internal insulation 310 can be of a high dielectricconstant. As the skin resistance between the electrodes (labeled as Aand E in FIG. 6) is normally significantly higher than that of thetissue (labeled as C in FIG. 6) underneath it (1-10 KO vs. 0.1-1 KO),most of the potential drop beyond the isolects occurs there. Toaccommodate for these impedances (Z), the characteristics of theinternal insulation 310 (labeled as B and D in FIG. 6) should be suchthat they have impedance preferably under 100 KO at the frequencies ofthe present TC fields (e.g., 50 KHz to 500 KHz). For example, if it isdesired for the impedance to be about 10K Ohms or less, such that over1% of the applied voltage falls on the tissues, for isolects with asurface area of 10 mm², at frequencies of 200 KHz, the capacity shouldbe on the order of 10⁻¹⁰ F, which means that using standard insulationswith a dielectric constant of 2-3, the thickness of the insulating layer310 should be about 50-100 microns. An internal field 10 times strongerwould be obtained with insulators with a dielectric constant of about20-50.

Since the thin insulating layer can be very vulnerable, etc., theinsulation can be replaced by very high dielectric constant insulatingmaterials, such as titanium dioxide (e.g., rutil), the dielectricconstant can reach values of about 200. There a number of differentmaterials that are suitable for use in the intended application and havehigh dielectric constants. For example, some materials include: lithiumnibate (LiNbO₃), which is a ferroelectric crystal and has a number ofapplications in optical, pyroelectric and piezoelectric devices; yttriumiron garnet (YIG) is a ferromagnetic crystal and magneto-opticaldevices, e.g., optical isolator can be realized from this material;barium titanate (BaTiO₃) is a ferromagnetic crystal with a largeelectro-optic effect; potassium tantalate (kTaO₃) which is a dielectriccrystal (ferroelectric at low temperature) and has very low microwaveloss and tunability of dielectric constant at low temperature; andlithium tantalate (LiTaO₃) which is a ferroelectric crystal with similarproperties as lithium niobate and has utility in electro-optical,pyroelectric and piezoelectric devices. It will be understood that theaforementioned exemplary materials can be used in combination with thepresent device where it is desired to use a material having a highdielectric constant.

One must also consider another factor that effects the effectivecapacity of the isolects 230, namely the presence of air between theisolects 230 and the skin. Such presence, which is not easy to prevent,introduces a layer of an insulator with a dielectric constant of 1.0, afactor that significantly lowers the effective capacity of the isolects230 and neutralizes the advantages of the titanium dioxide (rutil), etc.To overcome this problem, the isolects 230 can be shaped so as toconform with the body structure and/or (2) an intervening filler 270 (asillustrated in FIG. 10C), such as a gel, that has high conductance and ahigh effective dielectric constant, can be added to the structure. Theshaping can be pre-structured (see FIG. 10A) or the system can be madesufficiently flexible so that shaping of the isolects 230 is readilyachievable. The gel can be contained in place by having an elevated rimas depicted in FIG. 10C. The gel can be made of hydrogels, gelatins,agar, etc., and can have salts dissolved in it to increase itsconductivity. FIGS. 10A-10C illustrate various exemplary configurationsfor the isolects 230. The exact thickness of the gel is not important solong as it is of sufficient thickness that the gel layer does not dryout during the treatment. In one exemplary embodiment, the thickness ofthe gel is about 0.5 mm to about 2 mm.

In order to achieve the desirable features of the isolects 230, thedielectric coating of each should be very thin, for example from between1-50 microns. Since the coating is so thin, the isolects 230 can easilybe damaged mechanically. This problem can be overcome by adding aprotective feature to the isolect's structure so as to provide desiredprotection from such damage. For example, the isolect 230 can be coated,for example, with a relatively loose net 340 that prevents access to thesurface but has only a minor effect on the effective surface area of theisolect 230 (i.e., the capacity of the isolects 230 (cross sectionpresented in FIG. 12B). The loose net 340 does not effect the capacityand ensures good contact with the skin, etc. The loose net 340 can beformed of a number of different materials; however, in one exemplaryembodiment, the net 340 is formed of nylon, polyester, cotton, etc.Alternatively, a very thin conductive coating 350 can be applied to thedielectric portion (insulating layer) of the isolect 230. One exemplaryconductive coating is formed of a metal and more particularly of gold.The thickness of the coating 350 depends upon the particular applicationand also on the type of material used to form the coating 350; however,when gold is used, the coating has a thickness from about 0.1 micron toabout 0.1 mm. Furthermore, the rim illustrated in FIG. 10 can alsoprovide some mechanical protection.

However, the capacity is not the only factor to be considered. Thefollowing two factors also influence how the isolects 230 areconstructed. The dielectric strength of the internal insulating layer310 and the dielectric losses that occur when it is subjected to the TCfield, i.e., the amount of heat generated. The dielectric strength ofthe internal insulation 310 determines at what field intensity theinsulation will be “shorted” and cease to act as an intact insulation.Typically, insulators, such as plastics, have dielectric strength valuesof about 100V per micron or more. As a high dielectric constant reducesthe field within the internal insulator 310, a combination of a highdielectric constant and a high dielectric strength gives a significantadvantage. This can be achieved by using a single material that has thedesired properties or it can be achieved by a double layer with thecorrect parameters and thickness. In addition, to further decreasing thepossibility that the insulating layer 310 will fail, all sharp edges ofthe insulating layer 310 should be eliminated as by rounding thecorners, etc., as illustrated in FIG. 10D using conventional techniques.

FIGS. 8 and 9 illustrate a second type of treatment using the isolects230, namely electric field generation by internal isolects 230. A bodyto which the isolects 230 are implanted is generally indicated at 311and includes a skin surface 313 and a tumor 315. In this embodiment, theisolects 230 can have the shape of plates, wires or other shapes thatcan be inserted subcutaneously or a deeper location within the body 311so as to generate an appropriate field at the target area (tumor 315).

It will also be appreciated that the mode of isolects application is notrestricted to the above descriptions. In the case of tumors in internalorgans, for example, liver, lung, etc., the distance between each memberof the pair of isolects 230 can be large. The pairs can even bypositioned opposite sides of a torso 410, as illustrated in FIG. 11. Thearrangement of the isolects 230 in FIG. 11 is particularly useful fortreating a tumor 415 associated with lung cancer or gastrointestinaltumors. In this embodiment, the electric fields (TC fields) spread in awide fraction of the body.

In order to avoid overheating of the treated tissues, a selection ofmaterials and field parameters is needed. The isolects insulatingmaterial should have minimal dielectric losses at the frequency rangesto be used during the treatment process. This factor can be taken intoconsideration when choosing the particular frequencies for thetreatment. The direct heating of the tissues will most likely bedominated by the heating due to current flow (given by the I*R product).In addition, the isolect (insulated electrode) 230 and its surroundingsshould be made of materials that facilitate heat losses and its generalstructure should also facilitate head losses, i.e., minimal structuresthat block heat dissipation to the surroundings (air) as well as highheat conductivity.

The effectiveness of the treatment can be enhanced by an arrangement ofisolects 230 that focuses the field at the desired target while leavingother sensitive areas in low field density (i.e., protected areas). Theproper placement of the isolects 230 over the body can be maintainedusing any number of different techniques, including using a suitablepiece of clothing that keeps the isolects at the appropriate positions.FIG. 13 illustrates such an arrangement in which an area labeled as “P”represents a protected area. The lines of field force do not penetratethis protected area and the field there is much smaller than near theisolects 230 where target areas can be located and treated well. Incontrast, the field intensity near the four poles is very high.

The following Example serves to illustrate an exemplary application ofthe present apparatus and application of TC fields; however, thisExample is not limiting and does not limit the scope of the presentinvention in any way.

EXAMPLE

To demonstrate the effectiveness of electric fields having the abovedescribed properties (e.g., frequencies between 50 KHz and 500 KHz) indestroying tumor cells, the electric fields were applied to treat micewith malignant melanoma tumors. Two pairs of isolects 230 werepositioned over a corresponding pair of malignant melanomas. Only onepair was connected to the generator 210 and 200 KHz alternating electricfields (TC fields) were applied to the tumor for a period of 6 days. Onemelanoma tumor was not treated so as to permit a comparison between thetreated tumor and the non-treated tumor. After treatment for 6 days, thepigmented melanoma tumor remained clearly visible in the non-treatedside of the mouse, while, in contrast, no tumor is seen on the treatedside of the mouse. The only areas that were visible discernable on theskin were the marks that represented the points of insertion of theisolects 230. The fact that the tumor was eliminated at the treated sidewas further demonstrated by cutting and inversing the skin so that itsinside face was exposed. Such a procedure indicated that the tumor hasbeen substantially, if not completely, eliminated on the treated side ofthe mouse. The success of the treatment was also further verified bypathhistological examination.

The present inventor has thus uncovered that electric fields havingparticular properties can be used to destroy dividing cells or tumorswhen the electric fields are applied to using an electronic device. Morespecifically, these electric fields fall into a special intermediatecategory, namely bio-effective fields that have no meaningfulstimulatory and no thermal effects, and therefore overcome thedisadvantages that were associated with the application of conventionalelectric fields to a body. It will also be appreciated that the presentapparatus can further include a device for rotating the TC fieldrelative to the living tissue. For example and according to oneembodiment, the alternating electric potential applies to the tissuebeing treated is rotated relative to the tissue using conventionaldevices, such as a mechanical device that upon activation, rotatesvarious components of the present system.

Moreover and according to yet another embodiment, the TC fields areapplied to different pairs of the insulated electrodes 230 in aconsecutive manner. In other words, the generator 210 and the controlsystem thereof can be arranged so that signals are sent at periodicintervals to select pairs of insulated electrodes 230, thereby causingthe generation of the TC fields of different directions by theseinsulated electrodes 230. Because the signals are sent at select timesfrom the generator to the insulated electrodes 230, the TC fields ofchanging directions are generated consecutively by different insulatedelectrodes 230. This arrangement has a number of advantages and isprovided in view of the fact that the TC fields have maximal effect whenthey are parallel to the axis of cell division. Since the orientation ofcell division is in most cases random, only a fraction of the dividingcells are affected by any given field. Thus, using fields of two or moreorientations increases the effectiveness since it increases the chancesthat more dividing cells are affected by a given TC field.

Turning now to FIG. 14 in which an article of clothing 500 according toone exemplary embodiment is illustrated. More specifically, the articleof clothing 500 is in the form of a hat or cap or other type of clothingdesigned for placement on a head of a person. For purposes ofillustration, a head 502 is shown with the hat 500 being placed thereonand against a skin surface 504 of the head 502. An intra-cranial tumoror the like 510 is shown as being formed within the head 502 underneaththe skin surface 504 thereof. The hat 500 is therefore intended forplacement on the head 502 of a person who has a tumor 510 or the like.

Unlike the various embodiments illustrated in FIGS. 1-13 where theinsulated electrodes 230 are arranged in a more or less planararrangement since they are placed either on a skin surface or embeddedwithin the body underneath it, the insulated electrodes 230 in thisembodiment are specifically contoured and arranged for a specificapplication. The treatment of intra-cranial tumors or other lesions orthe like typically requires a treatment that is of a relatively longduration, e.g., days to weeks, and therefore, it is desirable to provideas much comfort as possible to the patient. The hat 500 is specificallydesigned to provide comfort during the lengthy treatment process whilenot jeopardizing the effectiveness of the treatment.

According to one exemplary embodiment, the hat 500 includes apredetermined number of insulated electrodes 230 that are preferablypositioned so as to produce the optimal TC fields at the location of thetumor 510. The lines of force of the TC field are generally indicated at520. As can be seen in FIG. 14, the tumor 500 is positioned within theselines of force 520. As will be described in greater detail hereinafter,the insulated electrodes 230 are positioned within the hat 500 such thata portion or surface thereof is free to contact the skin surface 504 ofthe head 502. In other words, when the patient wears the hat 500, theinsulated electrodes 230 are placed in contact with the skin surface 504of the head 502 in positions that are selected so that the TC fieldsgenerated thereby are focused at the tumor 510 while leaving surroundingareas in low density. Typically, hair on the head 502 is shaved inselected areas to permit better contact between the insulated electrodes230 and the skin surface 504; however, this is not critical.

The hat 500 preferably includes a mechanism 530 that applies or force tothe insulated electrodes 230 so that they are pressed against the skinsurface 502. For example, the mechanism 530 can be of a biasing typethat applies a biasing force to the insulated electrodes 230 to causethe insulated electrodes 230 to be directed outwardly away from the hat500. Thus, when the patient places the hat 500 on his/her head 502, theinsulated electrodes 230 are pressed against the skin surface 504 by themechanism 530. The mechanism 530 can slightly recoil to provide acomfortable fit between the insulated electrodes 230 and the head 502.In one exemplary embodiment, the mechanism 530 is a spring based devicethat is disposed within the hat 500 and has one section that is coupledto and applies a force against the insulated electrodes 230.

As with the prior embodiments, the insulated electrodes 230 are coupledto the generator 210 by means of conductors 220. The generator 210 canbe either disposed within the hat 500 itself so as to provide a compact,self-sufficient, independent system or the generator 210 can be disposedexternal to the hat 500 with the conductors 220 exiting the hat 500through openings or the like and then running to the generator 210. Whenthe generator 210 is disposed external to the hat 500, it will beappreciated that the generator 210 can be located in any number ofdifferent locations, some of which are in close proximity to the hat 500itself, while others can be further away from the hat 500. For example,the generator 210 can be disposed within a carrying bag or the like(e.g., a bag that extends around the patient's waist) which is worn bythe patient or it can be strapped to an extremity or around the torso ofthe patient. The generator 210 can also be disposed in a protective casethat is secured to or carried by another article of clothing that isworn by the patient. For example, the protective case can be insertedinto a pocket of a sweater, etc. FIG. 14 illustrates an embodiment wherethe generator 210 is incorporated directly into the hat 500.

Turning now to FIGS. 15 and 16, in one exemplary embodiment, a number ofinsulated electrodes 230 along with the mechanism 530 are preferablyformed as an independent unit, generally indicated at 540, that can beinserted into the hat 500 and electrically connected to the generator(not shown) via the conductors (not shown). By providing these membersin the form of an independent unit, the patient can easily insert and/orremove the units 540 from the hat 500 when they may need cleaning,servicing and/or replacement.

In this embodiment, the hat 500 is constructed to include select areas550 that are formed in the hat 500 to receive and hold the units 540.For example and as illustrated in FIG. 15, each area 550 is in the formof an opening (pore) that is formed within the hat 500. The unit 540 hasa body 542 and includes the mechanism 530 and one or more insulatedelectrodes 230. The mechanism 530 is arranged within the unit 540 sothat a portion thereof (e.g., one end thereof) is in contact with a faceof each insulated electrode 230 such that the mechanism 530 applies abiasing force against the face of the insulated electrode 230. Once theunit 540 is received within the opening 550, it can be securely retainedtherein using any number of conventional techniques, including the useof an adhesive material or by using mechanical means. For example, thehat 500 can include pivotable clip members that pivot between an openposition in which the opening 550 is free and a closed position in whichthe pivotable clip members engage portions (e.g., peripheral edges) ofthe insulated electrodes to retain and hold the insulated electrodes 230in place. To remove the insulated electrodes 230, the pivotable clipmembers are moved to the open position. In the embodiment illustrated inFIG. 16, the insulated electrodes 230 are retained within the openings550 by an adhesive element 560 which in one embodiment is a two sidedself-adhesive rim member that extends around the periphery of theinsulated electrode 230. In other words, a protective cover of one sideof the adhesive rim 560 is removed and it is applied around theperiphery of the exposed face of the insulated electrode 230, therebysecurely attaching the adhesive rim 560 to the hat 500 and then theother side of the adhesive rim 560 is removed for application to theskin surface 504 in desired locations for positioning and securing theinsulated electrode 230 to the head 502 with the tumor being positionedrelative thereto for optimization of the TC fields. Since one side ofthe adhesive rim 560 is in contact with and secured to the skin surface540, this is why it is desirable for the head 502 to be shaved so thatthe adhesive rim 560 can be placed fleshly against the skin surface 540.

The adhesive rim 560 is designed to securely attach the unit 540 withinthe opening 550 in a manner that permits the unit 540 to be easilyremoved from the hat 500 when necessary and then replaced with anotherunit 540 or with the same unit 540. As previously mentioned, the unit540 includes the biasing mechanism 530 for pressing the insulatedelectrode 230 against the skin surface 504 when the hat 500 is worn. Theunit 540 can be constructed so that the side opposite the insulatedelectrode 230 is a support surface formed of a rigid material, such asplastic, so that the biasing mechanism 530 (e.g., a spring) can becompressed therewith under the application of force and when the spring530 is in a relaxed state, the spring 530 remains in contact with thesupport surface and the applies a biasing force at its other end againstthe insulated electrode 230. The biasing mechanism 530 (e.g., spring)preferably has a contour corresponding to the skin surface 504 so thatthe insulated electrode 230 has a force applied thereto to permit theinsulated electrode 230 to have a contour complementary to the skinsurface 504, thereby permitting the two to seat fleshly against oneanother. While the mechanism 530 can be a spring, there are a number ofother embodiments that can be used instead of a spring. For example, themechanism 530 can be in the form of an elastic material, such as a foamrubber, a foam plastic, or a layer containing air bubbles, etc.

The unit 540 has an electric connector 570 that can be hooked up to acorresponding electric connector, such as a conductor 220, that isdisposed within the hat 500. The conductor 220 connects at one end tothe unit 540 and at the other end is connected to the generator 210. Thegenerator 210 can be incorporated directly into the hat 500 or thegenerator 210 can be positioned separately (remotely) on the patient oron a bedside support, etc.

As previously discussed, a coupling agent, such as a conductive gel, ispreferably used to ensure that an effective conductive environment isprovided between the insulated electrode 230 and the skin surface 504.Suitable gel materials have been disclosed hereinbefore in thediscussion of earlier embodiments. The coupling agent is disposed on theinsulated electrode 230 and preferably, a uniform layer of the agent isprovided along the surface of the electrode 230. One of the reasons thatthe units 540 need replacement at periodic times is that the couplingagent needs to be replaced and/or replenished. In other words, after apredetermined time period or after a number of uses, the patient removesthe units 540 so that the coupling agent can be applied again to theelectrode 230.

FIGS. 17 and 18 illustrate another article of clothing which has theinsulated electrodes 230 incorporated as part thereof. Morespecifically, a bra or the like 700 is illustrated and includes a bodythat is formed of a traditional bra material, generally indicated at705, to provide shape, support and comfort to the wearer. The bra 700also includes a fabric support layer 710 on one side thereof. Thesupport layer 710 is preferably formed of a suitable fabric materialthat is constructed to provide necessary and desired support to the bra700.

Similar to the other embodiments, the bra 700 includes one or moreinsulated electrodes 230 disposed within the bra material 705. The oneor more insulated electrodes are disposed along an inner surface of thebra 700 opposite the support 710 and are intended to be placed proximateto a tumor or the like that is located within one breast or in theimmediately surrounding area. As with the previous embodiment, theinsulated electrodes 230 in this embodiment are specifically constructedand configured for application to a breast or the immediate area. Thus,the insulated electrodes 230 used in this application do not have aplanar surface construction but rather have an arcuate shape that iscomplementary to the general curvature found in a typical breast.

A lining 720 is disposed across the insulated electrodes 230 so as toassist in retaining the insulated electrodes in their desired locationsalong the inner surface for placement against the breast itself. Thelining 720 can be formed of any number of thin materials that arecomfortable to wear against one's skin and in one exemplary embodiment,the lining 720 is formed of a fabric material.

The bra 700 also preferably includes a biasing mechanism 800 as in someof the earlier embodiments. The biasing mechanism 800 is disposed withinthe bra material 705 and extends from the support 710 to the insulatedelectrode 230 and applies a biasing force to the insulated electrode 230so that the electrode 230 is pressed against the breast. This ensuresthat the insulated electrode 230 remains in contact with the skinsurface as opposed to lifting away from the skin surface, therebycreating a gap that results in a less effective treatment since the gapdiminishes the efficiency of the TC fields. The biasing mechanism 800can be in the form of a spring arrangement or it can be an elasticmaterial that applies the desired biasing force to the insulatedelectrodes 230 so as to press the insulated electrodes 230 into thebreast. In the relaxed position, the biasing mechanism 800 applies aforce against the insulated electrodes 230 and when the patient placesthe bra 700 on their body, the insulated electrodes 230 are placedagainst the breast which itself applies a force that counters thebiasing force, thereby resulting in the insulated electrodes 230 beingpressed against the patient's breast. In the exemplary embodiment thatis illustrated, the biasing mechanism 800 is in the form of springs thatare disposed within the bra material 705.

A conductive gel 810 can be provided on the insulated electrode 230between the electrode and the lining 720. The conductive gel layer 810is formed of materials that have been previously described herein forperforming the functions described above.

An electric connector 820 is provided as part of the insulated electrode230 and electrically connects to the conductor 220 at one end thereof,with the other end of the conductor 220 being electrically connected tothe generator 210. In this embodiment, the conductor 220 runs within thebra material 705 to a location where an opening is formed in the bra700. The conductor 220 extends through this opening and is routed to thegenerator 210, which in this embodiment is disposed in a location remotefrom the bra 700. It will also be appreciated that the generator 210 canbe disposed within the bra 700 itself in another embodiment. Forexample, the bra 700 can have a compartment formed therein which isconfigured to receive and hold the generator 210 in place as the patientwears the bra 700. In this arrangement, the compartment can be coveredwith a releasable strap that can open and close to permit the generator210 to be inserted therein or removed therefrom. The strap can be formedof the same material that is used to construct the bra 700 or it can beformed of some other type of material. The strap can be releasablyattached to the surrounding bra body by fastening means, such as a hookand loop material, thereby permitting the patient to easily open thecompartment by separating the hook and loop elements to gain access tothe compartment for either inserting or removing the generator 210.

The generator 210 also has a connector 211 for electrical connection tothe conductor 220 and this permits the generator 210 to be electricallyconnected to the insulated electrodes 230.

As with the other embodiments, the insulated electrodes 230 are arrangedin the bra 700 to focus the electric field (TC fields) on the desiredtarget (e.g., a tumor). It will be appreciated that the location of theinsulated electrodes 230 within the bra 700 will vary depending upon thelocation of the tumor. In other words, after the tumor has been located,the physician will then devise an arrangement of insulated electrodes230 and the bra 700 is constructed in view of this arrangement so as tooptimize the effects of the TC fields on the target area (tumor). Thenumber and position of the insulated electrodes 230 will thereforedepend upon the precise location of the tumor or other target area thatis being treated. Because the location of the insulated electrodes 230on the bra 700 can vary depending upon the precise application, theexact size and shape of the insulated electrodes 230 can likewise vary.For example, if the insulated electrodes 230 are placed on the bottomsection of the bra 700 as opposed to a more central location, theinsulated electrodes 230 will have different shapes since the shape ofthe breast (as well as the bra) differs in these areas.

FIG. 19 illustrates yet another embodiment in which the insulatedelectrodes 230 are in the form of internal electrodes that areincorporated into in the form of a probe or catheter 600 that isconfigured to enter the body through a natural pathway, such as theurethra, vagina, etc. In this embodiment, the insulated electrodes 230are disposed on an outer surface of the probe 600 and along a lengththereof. The conductors 220 are electrically connected to the electrodes230 and run within the body of the probe 600 to the generator 210 whichcan be disposed within the probe body or the generator 210 can bedisposed independent of the probe 600 in a remote location, such as onthe patient or at some other location close to the patient.

Alternatively, the probe 600 can be configured to penetrate the skinsurface or other tissue to reach an internal target that lies within thebody. For example, the probe 600 can penetrate the skin surface and thenbe positioned adjacent to or proximate to a tumor that is located withinthe body.

In these embodiments, the probe 600 is inserted through the naturalpathway and then is positioned in a desired location so that theinsulated electrodes 230 are disposed near the target area (i.e., thetumor). The generator 210 is then activated to cause the insulatedelectrodes 230 to generate the TC fields which are applied to the tumorfor a predetermined length of time. It will be appreciated that theillustrated probe 600 is merely exemplary in nature and that the probe600 can have other shapes and configurations so long as they can performthe intended function. Preferably, the conductors (e.g., wires) leadingfrom the insulated electrodes 230 to the generator 210 are twisted orshielded so as not to generate a field along the shaft.

FIG. 20 illustrates yet another embodiment in which a high standingcollar member 900 (or necklace type structure) can be used to treatthyroid, parathyroid, laryngeal lesions, etc. FIG. 20 illustrates thecollar member 900 in an unwrapped, substantially flat condition. In thisembodiment, the insulated electrodes 230 are incorporated into a body910 of the collar member 900 and are configured for placement against aneck area of the wearer. The insulated electrodes 230 are coupled to thegenerator 210 according to any of the manner described hereinbefore andit will be appreciated that the generator 210 can be disposed within thebody 910 or it can be disposed in a location external to the body 910.The collar body 910 can be formed of any number of materials that aretraditionally used to form collars 900 that are disposed around aperson's neck. As such, the collar 900 preferably includes a means 920for adjusting the collar 900 relative to the neck. For example,complementary fasteners (hook and loop fasteners, buttons, etc.) can bedisposed on ends of the collar 900 to permit adjustment of the collardiameter.

Thus, the construction of the present devices are particularly wellsuited for applications where the devices are incorporated into articlesof clothing to permit the patient to easily wear a traditional articleof clothing while at the same time the patient undergoes treatment. Inother words, an extra level of comfort can be provided to the patientand the effectiveness of the treatment can be increased by incorporatingsome or all of the device components into the article of clothing. Theprecise article of clothing that the components are incorporated intowill obviously vary depending upon the target area of the living tissuewhere tumor, lesion or the like exists. For example, if the target areais in the testicle area of a male patient, then an article of clothingin the form of a sock-like structure or wrap can be provided and isconfigured to be worn around the testicle area of the patient in such amanner that the insulated electrodes thereof are positioned relative tothe tumor such that the TC fields are directed at the target tissue. Theprecise nature or form of the article of clothing can vary greatly sincethe device components can be incorporated into most types of articles ofclothing and therefore, can be used to treat any number of differentareas of the patient's body where a condition may be present.

While the invention has been particularly shown and described withreference to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details can bemade without departing from the spirit and scope of the invention.

1. A probe for treatment of a section of living tissue by selectivelydestroying dividing cells of a target section of tissue, the dividingcells having polarizable or polar intracellular members, the probecomprising: a probe body for insertion into a body; at least twoinsulated electrodes disposed on an outer surface of the probe body; andan electric field source for applying an alternating electric potentialacross the at least two insulated electrodes to create a condition inthe dividing cells that encourages the destruction thereof.
 2. The probeof claim 1, wherein the probe body is configured to be inserted into andpass through a natural pathway of the body to position the insulatedelectrodes relative to the target section.
 3. The probe of claim 1,wherein the probe body is configured to penetrate the living tissue andbe positioned so that the electrodes are disposed proximate the targetsection.
 4. The probe of claim 3, wherein the probe body is configuredfor reception in a hypodermic needle.
 5. The probe of claim 1, whereinpassage of the electric field through the dividing cells in lateanaphase or telophase transforms the electric field into anon-homogenous electric field that produces an increased densityelectric field in a region of a cleavage furrow of the dividing cells,the non-homogeneous electric field produced within the dividing cellsbeing of sufficient intensity to move the polarizable, charged or polarintracellular members toward the cleavage.
 6. The probe of claim 1,wherein the first and second insulated electrodes have an arcuate shape.7. The probe of claim 1, wherein the electric field is a substantiallyuniform electric field prior to passing through the dividing cells. 8.The probe of claim 1, wherein the electric field source comprises agenerator that generates an alternating voltage waveform at frequenciesbetween about 50 KHz to about 500 KHz that activate each insulatedelectrode.
 9. The probe of claim 8, wherein the generator is disposedwithin the probe body.